1. Technical Field
The present invention relates generally to the field of bioresorbable copolymers, and more specifically to bioresorbable copolymers that can be tailored for specific applications, including but not limited to bioresorbable medical materials and tissue engineering.
2. Prior Art
Water-soluble, biocompatible, bioresorbable copolymers and methods of preparation and use of such copolymers have been known and used in the prior art. For examples, bioresorbable material implants can be used for sutures, prosthetic devices, and drug release matrices and in some examples need not be removed subsequent to their use. Bioresorbable polymers having reactive pendant groups are of particular interest. The incorporation of repeat units containing vicinal diols into, for example, polylactide polymers, may impart unique properties to the prepared materials, which can facilitate a variety of potential applications.
Polylactide polymers (hereinafter [L]-poly(lactic acid) or [L]-PLA), which are bioresorbable polymers, have shown favorable biocompatibility and have gained wide acceptability for applications that require bioresorption in vivo. The [L]-poly(lactic acid) polymers have been used for many years, and have proved to be sterilizable and of low toxicity. [L]-PLA is produced from lactic acid, either by the direct condensation of lactic acid or via the ring opening polymerization of lactide. Polylactide also is one of the most practicable materials as a biodegradable material with respect to its synthesis from renewable resources, useful physical properties, cost, environmental biodegradability, biocompatibility, and bioresorbability.
The mechanical and physicochemical properties of [L]-PLA polymers are dependent on the polymer structure. The degradation rate of [L]-PLA based polymeric materials is a function of the amorphous/crystalline and hydrophilic/hydrophobic properties. The introduction of carbonate linkages into a polymer chain is an effective way to attain a spectrum of properties such as degradation behaviors and mechanical performance. Strategies to regulate these factors have involved copolymerizations of [L]-lactide with [D]-lactide, glycolide, ethylene oxide, .epsilon.-caprolactone, and monomers that upon ring-opening provide amino acid repeat units.
The prior art discloses an array of examples that employ strategies to tailor PLA physico-mechanical properties and hydrolytic degradability by blending PLA with other polymers and copolymerizing [L]-lactide with other monomers. For example, U.S. Pat. No. 5066772 to Tang et al. discloses a bioresorbable copolymer that includes both carbonate repeating units and hydroxycarboxylic acid repeating esters units. Other examples of such copolymers are PLA polyesters with pendant carboxyl and amine functional groups such as those from malic acid and [L]-serine ester repeat units that have been disclosed by Ouchi et al., Makromol. Chem. 1989, 190 (1989) and, Zhou et al. Macromolecules, 23, 3399 (1990). Additionally, PLA polydepsipeptides with carboxyl, amino or thiol groups have also been published. ln't Veld et al., Makromol. Chem. 1992, 193, 2713 (1992).
The prior art discloses examples in which biopolymer chains are decorated to facilitate the attachment of various bioactive substances. Such decoration is recognized as being important in tissue engineering applications. Barrera et al., Macromolecules, 28, 425 (1995); Fietier et al., Polym. Bull. (Berlin) 24, 349 (1990). Barrera et al., Macromolecules, 28, 425 (1995), prepared a copolymer of poly(lactic acid-co-lysine) with RGD attached to the lysine residues at a surface concentration of 310 fmol/cm.sup.2. The RGD peptide functions to promote cell adhesion. However, the use of this copolymer has been restricted because the molecular weight of poly(lactic acid-co-lysine) copolymers decreased significantly relative to [L]-LA homopolymerization, even with low 3-[N-(carbonyl-benzoxy)-L-lysyl]-6-L-methyl-2,5-morpholinedione co-monomer feed ratios.
The prior art discloses a number of aliphatic polycarbonates or their copolymers that may be degradable. Examples cited in the literature include poly(ethylene carbonate) and poly(TMC). Kawaguchi et al., Chem. Pharm. Bull., 31, 1400, 4157 (1983); Nishida et al., Chem. Lett. 1994, 3, 421 (1994); Albertsson et al., Appl. Polym. Sci., 57 (1), 87 (1995), Zhu et al., Macromolecules, 24, 1736 (1991). Other degradable carbonate containing copolymers include TMC/LA, TMC/CL, and TMC or 2,2-dimethyl-TMC/butyrolactone. Grijpma et al., Macromol. Chem. Phys., 195, 1633 (1994), Buchholz, Mater. Sci., Mater. In Medicine, 4, 381 (1993).
The prior art discloses the introduction of functional entities into homo- and copolymers that are linked by carbonate or ester/carbonate bonds. For example, high molecular weight polycarbonates containing vinyl pendant groups were prepared by the homopolymerization of 4,4-cyclohexene-1,3-trimethylene carbonate. Chen et al., Macromolecules, 30, 3470 (1997). The vinyl pendant groups were partially or completely converted into epoxides by oxidation with chloroperoxybenzoic acid. Chen et al., Macromolecules, 30, 3470 (1997).
The prior art discloses a number of examples of bioresorbable copolymers comprising monomers with carboxylic acid. U.S. Pat. No. 6093792 to Gross discloses high molecular weight bioresorbable copolymers constructed to be useful for specific applications in the biomedical arts and includes a new cyclic carbonate monomer, 1,2-O-isopropylidene-D-xylofuranose-3,5-cyclic carbonate (IPXTC), and copolymers containing the new monomers, wherein the ketal groups were hydrolyzed to give copolymers of lactic acid and xylofuranose that have hydroxyl side groups. In addition, U.S. Pat. No. 5066772 to Tang et al. discloses a copolymer containing repeating units of carbonate and units of hydroxycarboxylic acid repeating esters that are bioresorbable. U.S. Pat. No. 4481353 to Nyilas et al. discloses a bioresorbable copolymer with polyesters composed of a Kreb Cycle intermediate and an alpha-hydroxy carboxylic acid from the group consisting of glycolic acid, L-lactic acid, and D-lactic acid.
The prior art discloses examples of polymers gaining a functional hydroxyl group after deprotection of the ketal group. For example, Tian et al. prepared 1,4,8-trioxaspiro [4,6]-9-undecanonone (or 5-ethylene ketal-caprolactone). Tian, et al., Macromolecules, 30, 406-409 (1997). The removal of the ketal protecting groups of repeat units from 5-ethylene ketal-caprolactone gave hydroxyl side chains. Vandanberg and co-workers prepared 2,2-dimethyl-5,5-bis(hydroxymethyl)-1,3-dioxane, which is the cyclic carbonate from the monoketal diol of pentaerythritol. Vandenberg, E. J. and Tian, D., Macromolecules, 32, 3613-3619 (1999). Deprotection led to a water-insoluble but water-swollen product.
The present reference and its incorporated references disclose copolymers and their constituents that are distinct from the prior art in ways including but not limited to structure and reactivity. One important distinction from the prior art is that the present invention comprises bioresorbable copolymers that contain 1,2-O-isopropylidene-3-benzyloxy-glucofuranose-4,4'-cyclic carbonate (IPGTC) and other bioresorbable comonomers such as lactide. In addition, this polymer is significantly more tailorable than the prior art polymers because of a novel built-in control allowing one, two or three free hydroxyl side groups in IPGTC repeats. This tailorable system is expected to have great value in the development of new bioresorbable medical materials. There is a need in the field of the present invention for the ability to strategically place functional groups that can facilitate covalent pro-drug attachment, cell targeting, control cell differentiation, and other biological and physical functions. Notwithstanding the prior art, there exists a need for a distinct bioresorbable material that is nontoxic, able to be thermally processed, and sufficiently flexible in structure to meet the needs for bioresorbable polymers.